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<p>A series of new methodologies to link a neurotransmitter receptor targeting vector (WAY) to carboranes and the preparation of the corresponding metallocarboranes (M = Re, ^99mTc) as a new class of organometallic CNS imaging probes is described. WAY-carboranes (<strong>5</strong>, <strong>6</strong>, <strong>16</strong>) and the corresponding metallocarboranes (M = Re (<strong>12</strong>, <strong>13</strong>, <strong>22a</strong>, <strong>22b</strong>), ^99mTc (<strong>14a</strong>, <strong>15</strong>, <strong>23</strong>)) were synthesized in yields ranging from 10-95%. The first observed 3,1,2 versus 2,1,8 rhenacarborane isomerization process was discovered for <strong>12</strong> where isomerization and complexation occurred simultaneously. Re-carboranes <strong>22a</strong> and <strong>22b</strong> had similar carbon-carbon cage configuration where electronic effects was the driving force behind isomerization.</p> <p>The lipophilicities of ^99mTc-carboranes (<strong>14a</strong>, <strong>15</strong>, <strong>23)</strong> were within the ideal range to cross the BBB (log P = 2.4-2.6). <em>In vitro</em> binding data showed that <strong>22b</strong> has high affinity for alpha-adrenergic receptors (K_i = 17-39 nM) resulting in the first organometallic complex to effectively bind to this class of receptors. SPECT images of <strong>14a</strong> in rats showed no brain uptake, while quantitative biodistribution studies indicated modest, non-negligible brain uptake in the hypothalamus region.</p> <p>The neutral [M(CO)₂(NO)(C₂B₉H₁₀R)] analogues (<strong>30</strong>, <strong>34</strong>, <strong>37</strong>) were prepared to address the limited brain uptake of the [M(CO)₃(C₂B₉H₁₀R)]^- complexes. Reactivity differences between Re and ^99mTc were noted during nitrosation conditions where the initial products from the reaction led to nitration of the phenyl group in addition to nitrosation of the metal core. The fluorescence properties of <strong>29</strong> were measured.</p> <p>Low yields and multistep syntheses associated with the preparation of substituted carborane led to the development of a carborane-alkyne platform. Alkyne-carboranes (<strong>53</strong>-<strong>55</strong>) were developed and conjugated to WAY-azide (<strong>46</strong>) using “click” chemistry. The metallocarboranes (M = Re (<strong>69</strong>-<strong>71</strong>), ^99mTc (<strong>72</strong>-<strong>74</strong>)) were generated in yields ranging from 45-71%.</p> / Doctor of Philosophy (PhD)

Antibiotic resistance has become and will continue to be a major medical issue of the 21st century. If not addressed, the potential for a post-antibiotic era could become a reality, one that the world has not been familiar with since the early 1900’s. Multidrug-resistant hospital-acquired bacterial infections already account for close to 2 million cases and 23,000 deaths in the United States, along with 20 billion dollars of additional medical spending each year. The CDC released a report in 2013 regarding the seriousness of antibiotic resistance and providing a snapshot of costs and mortality rates of the most serious antibiotic resistant bacteria, which includes 17 drug resistant bacteria, such as carbapenem-resistant Enterobacteriaceae, vancomycin-resistant Enterococcus and Staphylococcus aureus, and multidrug-resistant Acinetobacter and Pseudomonas aeruginosa. The development of antibiotic resistance is part of bacteria’s normal evolutionary process and thus impossible to completely stop. To ensure a future where resistant bacteria do not run rampant throughout society, there is a great need for new antibiotics and accordingly, methods to facilitate their discovery Macrolides are a class of antibiotics that target the bacterial ribosome. Since their discovery in the 1950’s medicinal chemistry has created semi-synthetic analogues of natural product macrolides to address poor pharmacokinetics and resistance. Modern X-Ray crystallography has allowed the chemist access to high resolution images of the bacterial ribosome bound to antibiotics including macrolides which has ushered in an era of structure-based design of novel antibiotics. These crystal structures suggest that the C-4 methyl group of third generation ketolide antibiotic telithromycin can sterically clash with a mutated rRNA residue causing loss of binding and providing a structural basis for resistance. The Andrade lab hypothesized that the replacement of this methyl group with hydrogen would alleviate the steric clash and allow the antibiotic to retain activity. To this end, the Andrade lab set out on a synthetic program to synthesize four desmethyl analogues of telithromycin by total synthesis that would directly test the steric clash hypothesis and also provide structure-activity relationships about these methyl groups which have not been assessed in the past. Following will contain highlights of the total synthesis of (-)-4,8,10-didesmethyl telithromycin, (-)-4,10-didesmethyl telithromycin, and (-)-4,8-desmethyl telithromycin and my journey toward the total synthesis of (-)-4-desmethyl telithromycin Traditional combinatorial chemistry uses chemical synthesis to make all possible molecules from various fragments. These molecules then need to be purified, characterized, and tested against the biological target of interest. While high-throughput assay technologies (i.e., automation) has streamlined this process to some extent, the process remains expensive when considering the costs of labor, reagents, and solvent to synthesize, purify, and characterize all library members. Unlike traditional combinatorial chemistry, in situ click chemistry directly employs the macromolecular target to template and synthesize its own inhibitor. In situ click chemistry makes use of the Huisgen cycloaddition of alkyne and azides to form 1,2,3-triazoles, which normally reacts slowly at room temperature in the absence of a catalyst. If azide and alkyne pairs can come together in a target binding pocket the activation energy of the reaction can be lowered and products detected by LC-MS. Compounds found in this way generally show tighter binding than the individual fragments. Described in the second part of this dissertation is the development of the first in situ click methodology targeting the bacterial ribosome. Using the triazole containing third generation ketolide solithromycin as a template we were able to successfully show that in situ click chemistry was able to predict the tightest binding compounds. / Chemistry

Carla Abarca Ph.D. Thesis / The selective separation of valuable minerals by froth flotation is a critical unit operation in mineral processing. Froth flotation is based on the ability of chemical reagents, called collectors, to selectively lower the surface energy of valuable mineral particles, facilitating attachment of the modified mineral particles to air bubbles in the flotation cell. The mineral laden bubbles rise to the surface forming a froth phase that can be isolated. Novel cationic polystyrene nanoparticle collectors have been developed recently to be used as effective flotation collectors, aiming to recover challenging nickel sulfide ores that respond poorly to conventional molecular flotation collectors. However, optimizing nanoparticle flotation collectors is a challenge. An effective nanoparticle collector candidate should meet three requirements: (1) it should be colloidally stable in the flotation media; (2) it should be hydrophobic enough to change the mineral surface and induce an air bubble-mineral particle attachment; and (3) specifically and strongly bind to metal-rich minerals. Producing nanoparticles that are simultaneously colloidally stable and sufficiently hydrophobic presents a problematic task. Thus, a delicate balance of nanoparticle properties is required for commercially viable nanoparticle collectors. This thesis presents a promising approach for discovering and characterizing novel nanoparticle collectors by using high throughput screening techniques. Developed was a workflow for fast fabrication and testing of nanoparticle candidates, including: (1) parallel production of large nanoparticle libraries covering a range of surface chemistries, (2) a high throughput colloidal stability assay to determine whether a nanoparticle type is stable in flotation conditions; (3) an automated contact angle assay to reject nanoparticles that are not hydrophobic enough to induce efficient bubble-particle attachment, and; (4) a laboratory flotation test in sodium carbonate (pH~10) with the best nanoparticle candidates. The automated colloidal stability assay was based on the optical characterization of diluted nanoparticle dispersions in multiwell plates, yielding critical coagulation concentrations (CCCs) of sodium carbonate. To pass this screening test, the CCC of candidate nanoparticles must be greater than the effective carbonate concentration in commercial flotation cells. Since the nanoparticle size affects the intrinsic light scattering properties of the nanoparticles, two routes were developed. The colloid stability assay was suitable for nanoparticles ranging between 50 nm and 500 nm, since nanoparticle size. The automated contact angle assay used a miniature 16-well plate format where flat glass slides were exposed to 200 μL nanoparticle dispersions. The cationic nanoparticles formed a saturated adsorbed monolayer on the glass, and after rinsing and drying, the water contact angle was automatically measured. Effective nanoparticle candidates had contact angles greater than 50 degrees, a criterion developed with model experiments. During the development of the automated workflow platform, a series of nanoparticles with methyl-ended PEG-methacrylate monomers were prepared. Although the PEG chains greatly enhanced colloidal stability, the particles were too hydrophilic to be effective collectors. Interestingly, nanoparticles with long PEG chains acted as froth modifiers, giving wetter and more robust foams as well as increased entrainment of materials that did not adhere to bubbles. Conventional laboratory scale latex synthesis methodologies are far too inefficient to generate large library of candidate nanoparticles. Instead, we started with a few parent nanoparticle types and then used Click chemistry to generate a large range of surface chemistries. Specifically copper-mediated azide alkyne cycloaddition reaction was used to functionalize the surface of azide nanoparticles with different chemical groups, ranging from hydrophilic amine-terminated PEG chains, to hydrophobic hexane-terminated materials. The Click library exhibited an extensive range of critical coagulation concentrations and contact angle values. For example, for a given parent azide nanoparticle, the contact angles ranged from 62 to 101 degrees, depending upon the density and type of click reagent. A novel paper chromatographic method was developed for the quantitative determination surface azide. This assay was critical for determining the surface density of functional groups from the click reactions. Overall, high throughput screening techniques were designed and applied to the development of nanoparticle collectors for froth flotation. Automated screening assays of critical coagulation concentration and contact angle proved to be effective in obtaining flotation domain maps, and finding the most promising nanoparticle collectors for froth flotation. I believe the work in this thesis is one of the first reported uses of high throughput methodologies for the development of mineral flotation reagents. / Thesis / Doctor of Philosophy (PhD) / Novel cationic polystyrene nanoparticle collectors have been developed to be used as effective flotation collectors, aiming to recover challenging nickel sulfide ores that respond poorly to conventional molecular flotation collectors. However, optimizing nanoparticle flotation collectors is a challenge. This thesis presents a promising approach for discovering and characterizing novel nanoparticle collectors by using high throughput screening techniques and click chemistry. Development of nanoparticle libraries and automated screening assays of critical coagulation concentration and contact angle proved to be effective in obtaining flotation domain maps, and finding the most promising nanoparticle collectors for froth flotation.

No / Functional, degradable polymers were synthesized via the copolymerization of vinyl acetate (VAc) and 2-methylene-1,3-dioxepane (MDO) using a macro-xanthate CTA, poly(N-vinylpyrrolidone), resulting in the formation of amphiphilic block copolymers of poly(NVP)-b-poly(MDO-co-VAc). The behavior of the block copolymers in water was investigated and resulted in the formation of self-assembled nanoparticles containing a hydrophobic core and a hydrophilic corona. The size of the resultant nanoparticles was able to be tuned with variation of the hydrophilic and hydrophobic segments of the core and corona by changing the incorporation of the macro-CTA as well as the monomer composition in the copolymers, as observed by Dynamic Light Scattering, Static Light Scattering, and Transmission Electron Microscopy analyses. The concept was further applied to a VAc derivative monomer, vinyl bromobutanoate, to incorporate further functionalities such as fluorescent dithiomaleimide groups throughout the polymer backbone using azidation and “click” chemistry as postpolymerization tools to create fluorescently labeled nanoparticles. / University of Warwick, BP, The Royal Society